AD is a devastating disease characterized by progressive memory loss, behavioral changes, loss of cognitive skills, and neurodegeneration. It is the most common form of dementia, with over 5.4 million victims in the United States alone. With our aging demographics, these numbers are predicted to rise dramatically unless effective therapeutics are developed. Indeed, if current trends continue, estimates indicate that there will be 16 million patients in the U.S. by 2050 with an annual cost exceeding $1 trillion.
Unfortunately, currently available anti-AD drugs are only minimally useful, at best. Even more problematic: clinical trials of new drugs under development are failing with regularity. As just two high-profile examples, the clinical trial of the “Aβ immunization” strategy had to be halted because of encephalitis. A more recent phase III trial employing an updated version of the same strategy (Bapineuzumab) showed no evidence of clinical benefit on either of the primary measures, one cognitive and one functional. While some have argued that these trials failed because the drugs were not administered early enough in the pathological process (Reiman et al., J. Alzheimers Dis., 26 Suppl 3:321-329 (2011)), antibody based strategies also suffer from very poor BBB permeability. Drug candidates with “disease-modifying” properties (e.g., targeting amyloid β (Aβ) and tau) are being investigated but clinical trials continue to fail (Giacobini and Gold. Nature Reviews Neurology (2013)).
Despite the above failures, the “amyloid hypothesis” remains a central and potentially cure-producing perspective for Alzheimer's. Indeed, Genentech, the NIH and the Banner Alzheimer's Institute have recently initiated a collaborative 5 year, $100 million dollar trial assessing the ability of Crenezumab, a humanized monoclonal antibody directed against Aβ, to prevent the onset of AD in a population that is pre-symptomatic but genetically destined to suffer early onset AD as a result of presenilin mutations. The rationale is to attempt to reduce the level of Aβ via the antibody.
Another important component of the (thus far unsuccessful) collective efforts to develop effective anti-AD therapeutics is that the research community was focused upon the wrong form of Aβ for many years. Specifically, it was believed for many years that the Aβ42 fibrils and plaques that scientists and physicians had been viewing in microscopes for nearly a century were the neurotoxic species. This may explain many failures in clinical trials including: small molecules: Tramiprosate, PBT1, PBT2, and ELND005 (scyllo-Inositol); and immunotherapies: bapineuzumab. In FIG. 1, the focus of these approaches would be the latter states of Aβ fibrils and β-sheets. However, it is now appreciated that the real agents of toxicity are early and soluble Aβ42 oligomers (Benilova et al., Nat. Neurosci., 15(3):349-357 (2012); Busche et al., Nat. Neurosci., 18(12):1725-1727 (2015); Dahlgren et al., Journal of Biological Chemistry 277(35):32046-32053 (2002); Hayden and Teplow, Alzheimers Res Ther. 5(6):60 (2013)).
Some progress is being made in characterizing different oligomeric stages of the amyloid cascade of Aβ, and immunologically distinct classes of oligomers have been identified using EPR and thioflavin T fluorescence. Additionally, new antibodies (Wu et al., Journal of Biological Chemistry 285(9):6071-6079 (2010)) are being developed, such as gammabodies (Perchiacca et al., Proceedings of the National Academy of Sciences 109(1):84-89 (2012)), that differentially recognize soluble oligomers of Aβ using novel grafted fragment methods. While each of these methods, and others, are powerful and informative, none of them is able to determine the distribution of soluble oligomer states nor identify the structures of these states. Further while some screening of potential inhibitors has been done (e.g., Meng et al., Biochemistry 49(37):8127-8133 (2010)), the analytical methods are indirect and most often use the inhibition of Aβ fibril formation as an assay, even though these fibrils are now known not to be the proximate toxic agent.
The present invention thus provides therapeutic small molecule agents useful for disruption of Aβ42 oligomer formation, in particular the dodecamer form of Aβ42, and for treatment of Alzheimer's disease.